Misuse preventative, controlled release formulation

ABSTRACT

Disclosed is a misuse preventative, controlled release formulation comprising a core comprising a superabsorbent material (for example, polycarbophil), a controlled release coat surrounding the core, and a plurality of controlled release microparticles having a pharmaceutically active agent (for example, an opioid analgesic) disposed within the core, the coat, or both the core and the coat. When crushed, either intentionally or accidentally, and exposed to an aqueous medium, the superabsorbent material present in the coreswells to encapsulate the microparticles, which remain substantially intact thereby retarding the release of the pharmaceutically active agent from the formulation. Also disclosed is a method of using the misuse preventative, controlled release formulation to deliver a pharmaceutically active agent to a mammal, for example, a human, in need thereof.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/195,813, filed Mar. 3, 2014, which is a continuation of U.S. patentapplication Ser. No. 13/919,476, filed Jun. 17, 2013, now U.S. Pat. No.8,691,270, which is a continuation of U.S. patent application Ser. No.12/336,495, filed Dec. 16, 2008, now U.S. Pat. No. 8,486,448, whichclaims the benefit of and priority to U.S. Provisional PatentApplication Ser. No. 61/014,296, filed Dec. 17, 2007, the entirecontents of each of which are incorporated by reference herein.

FIELD OF THE INVENTION

The present invention relates generally to a controlled releaseformulation for the delivery of at least one pharmaceutically activeagent, and more specifically, the invention relates to a misusepreventative, controlled release formulation, which maintains itscontrolled release properties for at least one pharmaceutically activeagent even when bisected or crushed and exposed to various media.

BACKGROUND OF THE INVENTION

Although significant developments have been made in the field of drugdelivery, concerns remain for drugs (for example, opioid analgesics)that are subject to abuse. Furthermore, the numbers of legitimatepatients misusing such drugs, either deliberately or accidentally,represents a serious medical problem. In particular, patient risk can beheightened when controlled release formulations are used because largeramounts of the pharmaceutically active agent typically are incorporatedinto these formulations to facilitate reduced dosing-frequency. However,while controlled release formulations may offer greater convenience andan improved adverse event profile, serious problems can occur if thecontrol release mechanism is compromised in any way, for example, byaccidental chewing or grinding of, or other damage to, the tablet, orco-ingestion with alcohol. Under these scenarios, immediate release ofthe pharmaceutically active agent followed by rapid absorption of up toa total daily dose of the pharmaceutical agent can have potentiallyfatal consequences.

While a number of approaches have been tried to address the abuse andmisuse of certain drugs, no effective approach has yet beencommercialized. To date, the approaches employed include, for example,deterrent formulations, agonist/antagonist formulations, and prodrugformulations.

Deterrent formulations are formulations that contain a noxioussubstance, such as, capsaicin, an emetic, or niacin. The aim is toprevent deliberate abuse by inflicting a painful or otherwise unpleasantreaction should the formulation be crushed or otherwise damaged prior toingestion. For example, U.S. Patent Publication Nos. 2003/0068370,2003/0068392 and 2007/0020188 describe incorporation of aversive agents(e.g., a bitter agent, an irritant, or an emetic agent) into a dosagecontaining an opioid analgesic. The aversive agents discourage an abuserfrom tampering with the dosage form and thereafter inhaling or injectingthe tampered dosage. The potential risk of such additives to thelegitimate user who accidentally damages the tablet is not addressed bysuch formulations.

Antagonist formulations contain inhibitors (antagonists) of thetherapeutic drug. When the formulation is crushed, the inhibitors areintended to prohibit or reverse the action of the pharmaceuticallyactive agent thereby reducing or eliminating any benefit for non-medicaluse. For example, naloxone is combined with pentazocine (Talwin®, soldby Sanofi-Winthrop) to deter parenteral abuse of pentazocine. Naloxoneis intended to block the binding of pentazocine to opioid receptors.Similarly, naloxone is added to a buprenorphine-containing formulation(Temgesic®, sold by Reckitt & Colman). It is understood, however, thatthis approach, can expose legitimate patients to unnecessary drugs, andcan potentially inhibit effective therapy because the inhibitors may bereleased during normal passage through the gastrointestinal tract. Theseformulations also assume that effective inhibition can be achieved(i.e., that the bioavailability, pharmacokinetics and relativeaffinities of the agonist and antagonist can be matched so as to eliciteffective inhibition in the intended recipient). U.S. Pat. Nos.3,773,955 and 3,966,940, for example, describe formulations containingcombinations of opioid agonists and antagonists, in which the antagonistdoes not block the therapeutic effect when the mixture is administeredorally but blocks analgesia, euphoria or physical dependence whenadministered parenterally in a crushed form by an abuser.

Prodrug formulations rely on in vivo metabolic conversion of the prodruginto the active drug by enzymes found, for example, in thegastrointestinal tract. While these formulations may prevent euphoriavia intravenous or nasal administration of the drug, they do not addressthe problems associated with potential intoxication (for example,alcohol intoxication) post oral administration.

Because of such limitations with existing technologies, there exists anongoing need for misuse preventative, controlled release formulationsthat can reduce the risk of intentional abuse and accidental misuse offormulations containing a pharmaceutically active agent.

SUMMARY OF THE INVENTION

The invention is based, in part, upon the discovery that it is possibleto create a drug delivery platform that permits the controlled releaseof a pharmaceutically active agent disposed within the formulation evenafter being sectioned (for example, bisected) or crushed. The platformis particularly useful for the administration of pharmaceutically activeagents that are capable of abuse and/or that have a narrow therapeuticindex. Agents capable of abuse, include, for example, analgesics (forexample, opioid analgesics), hypnotic agents, anxiolytic agents, centralnervous system (CNS) and respiratory stimulating agents, and agentshaving a narrow therapeutic index.

In one aspect, the invention provides a controlled release formulation,comprising: (a) a core comprising a superabsorbent material (forexample, polycarbophil); (b) a controlled release coat surrounding thecore; and (c) a plurality of controlled release microparticles having apharmaceutically active agent disposed therein, wherein themicroparticles are disposed within the core, the coat, or both the coreand the coat. As a result, the formulations are designed to have twocontrolled release mechanisms (the coat and the microparticles), whichwork together in an intact formulation. However, when crushed tocompromise the coating, the microparticles remain substantially intactto control the release of the pharmaceutically active agent and preventdose dumping.

If exposed to an aqueous environment, at least one pharmaceuticallyactive agent is released from the intact formulation over a prolongedperiod of time (for example, for at least 6 hours, at least 8 hours, atleast 12 hours, at least 18 hours, or at least 24 hours). In certainembodiments, at least 50%, preferably 60%, more preferably 70%, and evenmore preferably 80% of at least one pharmaceutically active agent isprevented from being released substantially immediately (for example,within 30 minutes) from the intact formulation.

If the formulation is crushed to break the controlled release coat andexpose the core, and then exposed to an aqueous environment, thesuperabsorbent material swells to create a hard, rigid gel that trapsthe microparticles, which remain substantially intact. The hard gelcreates an unpleasant experience if the crushed formulation is snortedup the nose and absorbs the nasal secretions that would otherwise permitabsorption via this route. Furthermore, once the hard gel has formedfollowing exposure to an extraction media, the resulting gel cannot bepushed through a needle of a syringe. Although the controlled releaseproperties of the coating may be compromised by crushing, themicroparticles still permit the controlled release of thepharmaceutically active agent and prevent the agent from being releasedsubstantially immediately from the formulation. In certain embodiments,at least 50%, preferably 60%, more preferably 70%, and even morepreferably 80% of at least one pharmaceutically active agent isprevented from being released substantially immediately (for example,within 30 minutes) from the formulation. As a result, the formulationsof the invention reduce or eliminate the potential for dose dumping inwater, alcohol (for example, ethanol), and other media of various pHeven if the formulations have been broken or crushed.

It is understood that in certain embodiments, the controlled releasemicroparticles can be disposed within the core or the coat. In otherembodiments, the controlled release microparticles (which can be thesame or different) are disposed within both the core and the coat. It isunderstood that the choice of location of the particles will depend uponthe release profile desired for the formulation. For example, if releaseover 8 hours is desired, then the particles may be located within thecoat. On the other hand, if release over 24 hours is desired, then theparticles may be located within the core, or within both the core andthe coat.

In certain embodiments, the core is monolithic. The monolithic coreoptionally comprises microparticles disposed therein. It is understood,however, that under certain circumstances the core can comprise aplurality of different release matrices, which can be, for example, inthe form of a bilayer or a multilayer that contains two, three or morelayers. In one bilayer embodiment, a first layer contains the drugcontaining microparticles and a second layer contains free drug (i.e.,drug not present in or associated with microparticles). As a result,drug is released faster from the second layer that lacks themicroparticles than from the first layer that contains themicroparticles. Furthermore, it is contemplated that, depending upon thedesired release profiles, one layer of the bilayer can contain one setof microparticles having one set of release kinetics and the other layerof the bilayer can contain a second, different set of microparticleshaving a second, different set of release kinetics.

In certain embodiments, the superabsorbent material is present such thatit constitutes about 10% (w/w) to about 70% (w/w) of the core. In otherembodiments, the superabsorbent material constitutes about 30% (w/w) toabout 50% (w/w) of the core. In addition, relative to the intactformulation, in certain embodiments, the volume of the core constitutesabout 5% to about 40% of the intact formulation, about 10% to about 30%of the intact formulation, or about 15% to about 20% of the intactformulation. In certain embodiments, the volume of the core constitutesat least 30%, at least 20%, or at least 15% of the final volume of theresulting intact formulation.

The controlled release microparticles comprise a controlled releasemedium (for example, cross-linked high amylose starch sold under theTradename CONTRAMID® from Labopharm, Inc., Laval, Canada) that controlsthe release of the pharmaceutically active agent disposed therein and/ora controlled release coating or film. The microparticles have an averagediameter in the range from about 1 μm to about 1000 μm. Themicroparticles, due to their small size and high radius of curvature,resist crushing when the formulation is crushed, for example, with aconventional pill crusher or between spoons or in a pestle and mortar.In one embodiment, the microparticles have an average diameter in therange from about of 200 μm to about 900 μm, or from about 300 μm toabout 800 μm. The microparticles under certain circumstances have anaverage diameter of about 700 μm. In another embodiment, the controlledrelease microparticles have an average diameter in the range of fromabout 1 μm to about 400 μm, from about 5 μm to about 300 μm, or fromabout 10 μm to about 200 μm. The microparticles can have an averagediameter of about 100 μm.

In addition, it is understood that the formulations can containmicroparticles that contain the same pharmaceutically active agent orthe same combination of two or more pharmaceutically active agents.Alternatively, the formulations can contain microparticles where onepopulation of microparticles contain one agent and another population ofmicroparticles contain a second, different agent.

In another aspect, the invention provides a method of providingcontrolled release of a pharmaceutically active agent to a mammal, forexample, a human. The method comprises orally administering to anindividual in need of the pharmaceutically active agent one or more ofthe controlled release formulations described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other objects, features and advantages of theinvention will become apparent from the following description ofpreferred embodiments, as illustrated in the accompanying drawings. Likereferenced elements identify common features in the correspondingdrawings. The drawings are not necessarily to scale, with emphasisinstead being placed on illustrating the principles of the presentinvention, in which:

FIGS. 1A-F show schematic representations of exemplary misusepreventative, controlled release formulations where controlled releasemicroparticles containing an agent of interest are disposed within thecoat (FIGS. 1A and 1D), the core (FIGS. 1B and 1E), or within both thecore and the coat (FIGS. 1C and 1F), wherein, in FIGS. 1A-1C, the coreis monolithic and in FIGS. 1D-1F, the core is a bilayer;

FIG. 2 is a graph showing the in vitro dissolution profile of TramadolHCl from an intact, exemplary controlled release formulation of theinvention in a U.S.P. Type I Apparatus in phosphate buffer pH 6.8;

FIG. 3 is a graph showing the in vitro dissolution profile of TramadolHCl from an intact, exemplary controlled release formulation of theinvention in a U.S.P. Type I Apparatus where the solvent is water (—□—),20% ethanol (—▪—), 40% ethanol (—Δ—), 60% ethanol (—▾—), 80% ethanol(—∘—) or 100% ethanol (——);

FIG. 4 is a graph showing the in vitro dissolution profile of TramadolHCl from an intact, exemplary controlled release formulation of theinvention in a U.S.P. Type I Apparatus as a function of pH where thesolvent is water (—▪—), buffer at pH 1.2 (——), buffer at pH 3.0 (—∘—),buffer at pH 5.0 (—▾—), or buffer at pH 6.8 (—Δ—);

FIG. 5 is a graph showing the in vitro dissolution profile of TramadolHCl from an intact, exemplary controlled release tablet of the invention(——) or from half a tablet (a bisected tablet) of the invention wherethe release values have been normalized relative to the intact tablet(—▪—) using a U.S.P. Type I Apparatus with phosphate buffer pH 6.8;

FIG. 6 is a photograph showing five vials, where the first vial contains2 mL of water and the second through the fifth vials (inverted) containdifferent tablets of controlled release formulations of the inventioneach of which had been crushed in a pill crusher and exposed to 2 mL ofwater to produce a hard gel that remained at the bottom of each vialeven when inverted;

FIG. 7 is a photograph showing seven inverted vials each containingcrushed tablets of the invention that had been exposed to 10 mL of (i)water at room temperature for 15 minutes with agitation (vial 1), (ii)water at 50° C. for 15 minutes with agitation (vial 2), (iii) water at75° C. for 15 minutes with agitation (vial 3), (iv) water at 100° C. for15 minutes with agitation (vial 4), (v) acidic media (pH 1.2) at roomtemperature for 15 minutes with agitation (vial 5), (vi) basic media (pH7.5) at room temperature for 15 minutes with agitation (vial 6), and(vii) 40% ethanol in water at room temperature for 15 minutes withagitation (vial 7);

FIG. 8 is a bar chart showing the effect of different ethanolconcentrations on Tramadol release from crushed tablets of the invention(bars with light shading) or Ultram ER (bar in dark shading) afterincubation in 900 mL of extraction media for 30 minutes at 37° C. in aU.S.P. Type I Apparatus;

FIG. 9 is a bar chart showing the effect of pH on Tramadol release fromcrushed tablets of the invention (bars with light shading) or Ultram ER(bar in dark shading) after incubation in 900 mL of extraction media ofvarious pH for 30 minutes at 37° C. in a U.S.P. Type I Apparatus.

FIGS. 10A and 10B are graphs showing the mean plasma concentration ofTramadol released from an exemplary 100 mg tablet following single-doseadministration to adult humans under fasting conditions (FIG. 10A) orunder fed conditions (FIG. 10B);

FIGS. 11A AND 11B are graphs showing the in vitro dissolution profilesof an embodiment containing 40 mg oxycodone HCl in a U.S.P. Type IApparatus at 100 rpm for twelve hours from either an intact tablet (FIG.11A) or a crushed tablet (FIG. 11B) in phosphate buffer pH 6.8 (——) orbuffer containing 40% ethanol (—□—);

FIG. 12 is a graph showing the in vitro dissolution profiles of anembodiment containing 40 mg oxycodone HCl in a U.S.P. Type I Apparatusat 100 rpm for twelve hours from either an intact tablet in phosphatebuffer pH 6.8 (——), or a bisected tablet in phosphate buffer pH 6.8(—Δ—);

FIG. 13 is a graph showing the in vitro dissolution profile of a coatedbilayer embodiment containing 20 mg oxycodone HCl/650 mg acetaminophen,where the release of oxycodone was measured in a U.S.P. Type I Apparatusat 100 rpm in acid at pH 1.2 for 1 hour and then in a phosphate bufferat pH 6.8 for 11 hours;

FIGS. 14A and 14B are graphs showing the in vitro dissolution profilesof an embodiment containing 150 mg Tramadol HCl in a U.S.P. Type IApparatus at 100 rpm in phosphate buffer pH 6.8 from three differentlots of intact tablets (FIG. 14A) or from crushed tablets (FIG. 14B);

FIGS. 15A and 15B are graphs showing the in vitro dissolution profilesof an embodiment containing 150 mg Tramadol HCl in a U.S.P. Type IApparatus at 100 rpm in water containing 60% ethanol from threedifferent lots of intact tablets (FIG. 15A) or from crushed tablets(FIG. 15B);

FIGS. 16A and 16B are graphs showing the in vitro dissolution profilesof an embodiment containing 200 mg Tramadol HCl in a U.S.P. Type IApparatus at 100 rpm in phosphate buffer pH 6.8 or water from eitherintact tablets (FIG. 16A) or from crushed tablets (FIG. 16B);

FIGS. 17A and 17B are graphs showing the in vitro dissolution profilesof an embodiment containing 200 mg Tramadol HCl in a U.S.P. Type IApparatus at 100 rpm in phosphate buffer pH 6.8 alone (——) or watercontaining 20% ethanol (—Δ—), 40% ethanol (—▪—), or 60% ethanol (—▾—)either from intact tablets (FIG. 17A) or from crushed tablets (FIG.17B); and

FIGS. 18A and 18B are graphs showing the in vitro dissolution profilesof an embodiment containing 30 mg hydrocodone in a U.S.P. Type IApparatus at 100 rpm in phosphate buffer pH 6.8 (——) or acid pH 1.2(—Δ—) either from intact tablets (FIG. 18A) or from crushed tablets(FIG. 18B).

DETAILED DESCRIPTION OF THE INVENTION

The invention is based, in part, upon the discovery that it is possibleto produce a controlled release platform that provides pharmaceuticalformulations less susceptible to intentional abuse and accidental misusethan other controlled release formulations and is free from noxiousadditives, active ingredient antagonists, prodrugs, and the like. Theformulations maintain their controlled release properties when sectioned(for example, bisected) as can happen, for example, when a subjectbreaks a tablet in half to make it easier to swallow. Furthermore, evenwhen crushed, the formulations of the invention prevent dose dumpingbecause the microparticles contained within the formulation remainsubstantially intact and retain their controlled release properties.

The invention provides a controlled release formulation, comprising: (a)a core comprising a superabsorbent material (for example,polycarbophil); (b) a controlled release coat surrounding the core; and(c) a plurality of controlled release microparticles having apharmaceutically active agent disposed therein, wherein themicroparticles are disposed within the core, the coat, or both the coreand the coat. The formulations have two controlled release mechanisms(the coat and the microparticles), which work together in an intactformulation. However, even when crushed to compromise the coating, themicroparticles remain substantially intact to control the release of thepharmaceutically active agent and prevent dose dumping. As used herein,the term “dose dumping” is understood to mean an uncontrolled release ofa pharmaceutically active agent where at least 80% of thepharmaceutically active agent in the formulation is released within 30minutes (a specification that can be used to characterize a formulationas an immediate release formulation).

FIGS. 1A-F show certain embodiments of the formulation of the invention.Each formulation 10 contains a core 20 and a coat 30. In FIGS. 1A and1D, formulation 10 contains controlled release microparticles 40 locatedwithin coat 30. In FIGS. 1B and 1E, formulation 10 contains controlledrelease microparticles 40 located within core 20. In FIGS. 1C and 1F,formulation 10 contains controlled release microparticles 40 locatedwithin both core 20 and coat 30. In FIGS. 1A-1C, the core is monolithic.In FIGS. 1D-1F, the core is shown to be a bilayer having a first layer50 and a second, different layer 60. It is understood, however, that thecore can comprise a multilayer having two or more (for example, three,four or more) layers of different materials. In each of the embodimentsshown in FIGS. 1A-F, the microparticles control the release of theactive ingredient irrespective of whether the tablet is intact orcompromised (for example, by bisection or crushing).

Under normal use, coat 30 protects core 20 from exposure to the solventthereby preventing the swelling of the superabsorbent material in thecore. As a result, the pharmaceutically active agent is releasedsteadily from the formulation. If drug containing controlled releasemicroparticles are located within coat 30, then the drug is releasedfrom coat 30 as the solvent permeates the coat. If drug containingcontrolled release microparticles are located within both coat 30 andcore 20, then the drug initially is released from the microparticles inthe coat. Over time, as the solvent gradually permeates through the coatand then accesses core 20, the drug is released from the microparticleslocated within the core. The formulations are designed so that coat 30maintains sufficient integrity (for example, the coat acts like a rigidor semi-rigid net) such that the superabsorbent material in core 20 isprevented from swelling and disrupting the integrity of the tablet.

It is contemplated that the compositions described herein can be usedfor the delivery of one or more (for example, two, three, four or more)pharmaceutically active agents. For example, the microparticles disposedin the core can contain a first pharmaceutically active agent andmicroparticles disposed in the coat can contain a second, differentpharmaceutically active agent. Alternatively, the microparticlesdisposed in the core and/or the coat can contain two or more differentpharmaceutically active agents. Furthermore, it is contemplated that thecore and/or the coat can comprise two or more different populations ofmicrospheres where each population contains the same or a differentpharmaceutically active agent. It is understood that the excipientspresent in each layer may vary. Furthermore, depending upon the releasekinetics desired, a pharmaceutically active agent can be disposed in thecore and/or the coat but not present within the microparticles. Forexample, a first pharmaceutically active agent disposed withinmicroparticles can be present in the coat but the same or differentpharmaceutically active agent not present in microparticles can bepresent in the core. Conversely, a first pharmaceutically active agentnot present in microparticles can be present in coat but the same ordifferent pharmaceutically active agent disposed in microparticles canbe present in the core.

In certain embodiments, the core is monolithic (see, FIGS. 1A-1C). Themonolithic core optionally can comprise microparticles disposed therein.It is understood, however, that under certain circumstances the core cancomprise a plurality of different release matrices, which can be, forexample, in the form of a bilayer or a multilayer that contains two,three or more layers (see, FIGS. 1D-1F). One of the layers can act canas an immediate release layer and another layer can act as a controlledrelease layer. Alternatively, at least two of the layers can havecontrolled release properties. In one embodiment, one layer can releaseone pharmaceutically active agent and another layer can release adifferent pharmaceutically active agent, which can be released at thesame or at different rates. In another embodiment, one layer can releaseone pharmaceutically active agent at one rate and another layer canrelease the same pharmaceutically active agent at a different rate(i.e., faster or slower than the first layer). In one bilayerembodiment, a first layer contains drug containing microparticles and asecond layer contains free drug (i.e., not contained within in orassociated with microparticles). As a result, the drug is releasedfaster from the second layer that lacks the microparticles than from thefirst layer that contains the microparticles. Furthermore, it iscontemplated that, depending upon the desired release profiles, onelayer of the bilayer can contain one population of microparticles havingone set of first release kinetics and the other layer of the bilayer cancontain a second, different population of microparticles having asecond, different set of release kinetics.

In the case of an intact formulation, when exposed to an aqueousenvironment (for example, a solution containing at least 10% (v/v)water), at least one pharmaceutically active agent is released from theintact formulation over a prolonged period of time (for example, for atleast 8 hours, at least 12 hours, at least 18 hours, or at least 24hours). In certain embodiments, at least 50%, preferably 60%, morepreferably 70%, and even more preferably 80% of at least onepharmaceutically active agent is prevented from being releasedsubstantially immediately (for example, within 30 minutes) from theformulation when exposed to an extraction medium, for example, water,aqueous solutions ranging in pH from 1.2 to 6.8, and different ethanolicmedia (for example, water containing 20% ethanol, 40% ethanol, 60%ethanol, or 80% ethanol and 100% ethanol). These features are shown, forexample, in FIGS. 2-4, which are discussed in more detail in Example 2.

When the formulation is bisected, for example, axially bisected, as canhappen when a patient breaks a tablet in half to make it easier toswallow, the controlled release coating becomes compromised. However,the combination of the residual coat surrounding the core, partialswelling of the core and the controlled release properties of themicroparticles permit the formulations to have a release profile of thepharmaceutically active agent substantially the same as the intacttablet. Furthermore, even when bisected, the formulations of theinvention permit the release of the pharmaceutically active agent overat least 12 hours, at least 18 hours, or over at least 24 hours. Incertain embodiments, at least 50%, preferably 60%, more preferably 70%,and even more preferably 80% of at least one pharmaceutically activeagent is prevented from being released substantially immediately (forexample, within 30 minutes) from the formulation when exposed to anextraction medium, for example, water, aqueous solutions ranging in pHfrom 1.2 to 6.8, and different ethanolic media (for example, watercontaining 20% ethanol, 40% ethanol, 60% ethanol, or 80% ethanol and100% ethanol). These features are shown, for example, in FIG. 5 and inFIG. 12.

When the formulation is crushed (for example, with a commerciallyavailable pill crusher to break formulation into at least 10 particlesor more) to break the controlled release coat and expose the core, andthen exposed to an aqueous environment, the superabsorbent materialswells rapidly (for example, within about 30 seconds) to create a hardgel that traps the microparticles. Based in part upon their small size(high radius of curvature), the microparticles resist the crushingprocess and remain substantially intact. The hard gel provides anunpleasant experience if the crushed formulation is snorted up a nostriland gel formation occurs within the nostril. This process has theadvantage that the nasal secretions needed for absorption of the activeingredient into the blood-stream are absorbed by the superabsorbentmaterial preventing intoxication via this route. Similarly, if theformulation is crushed and exposed to an aqueous environment to extractthe pharmaceutically active agent, the superabsorbant material in thecore can absorb the extraction medium leaving little or no extractionmedium to administer (see, FIGS. 6 and 7, which are discussed in Example4). In addition, the hard gel that is formed during this process isdifficult to draw or push though a syringe needle.

Although the controlled release properties of the coating arecompromised by crushing, the microparticles still permit the controlledrelease of the pharmaceutically active agent and prevent the agent frombeing released substantially immediately from the formulation (i.e., themicroparticles provide controlled release of the pharmaceutically activeagent). For example, at least 50%, preferably 60%, more preferably 70%,and even more preferably 80% of at least one pharmaceutically activeagent is prevented from being released substantially immediately (forexample, within 30 minutes) from the formulation (see, FIG. 8, which isdiscussed in Example 4). As a result, the formulations of the inventionprevent dose dumping in water, 20% ethanol, 40% ethanol, and 60% ethanoleven if the formulations have been broken or crushed.

In certain embodiments, the formulation of the invention, when crushedand exposed to 900 mL of water in a U.S.P. Type I Apparatus withstirring at 100 rpm for 30 minutes at 37° C., less than about 50%, lessthan about 45%, less than about 40%, less than about 35%, less thanabout 30%, less than about 25%, or less than about 20% by weight of atleast one pharmaceutically active agent originally present in theformulation before it was crushed broken is released into the water. Incertain other embodiments, when the formulation of the invention iscrushed and exposed to 900 mL of an aqueous solution containing 60%(v/v) ethanol in a U.S.P. Type I Apparatus with stirring at 100 rpm for30 minutes at 37° C., less than about 50%, less than about 45%, lessthan about 40%, less than about 35%, less than about 30%, less thanabout 25%, or less than about 20% by weight of at least onepharmaceutically active agent originally present in the formulationbefore it was broken is released into the aqueous solution.

Each of the components of the formulation of the invention are discussedin the following sections.

A. Considerations for the Core

The core comprises a superabsorbent material, which constitutes animportant feature of the invention. The term “superabsorbent material,”as used herein is understood to mean any material that absorbs solvent,for example, 1 gram of material absorbs at least 30 mL, more preferably50 mL of solvent, which, upon absorption of the solvent, swells toproduce a hydrated gel (hydrogel). In general, useful superabsorbentmaterials, when exposed to an aqueous medium (for example, water) absorbin excess of 10-15 times, such as at least greater than 30 times, morepreferably 50 times, of water based on its own weight. In certainembodiments, the superabsorbent material is a polymer.

Superabsorbent materials can be manufactured from polysaccharidederivatives or cross-linked polyelectrolytes. Polysaccharidesuperabsorbents include, but are not limited to, a starch graftcopolymer, a crosslinked carboxymethylcellulose derivative, across-linked hydroxypropyl distarch phosphate, a hydrolyzedstarch-acrylonitrile graft copolymer and a neutralized starch-acrylicacid graft copolymer. Cross-linked polyelectrolytes can containfunctional groups such as carboxyl, sulfonate, sulphate, sulfite,phosphate, amine, imine, amide, quaternary ammonium or a mixturethereof. Examples of polyelectrolyte polymers include, but are notlimited to, salts or partial salts of polyacrylic acid, polyacrylamidomethylpropane sulfonic acid, polyvinyl acetic acid, polyvinyl phosphonicacid, polyvinyl sulfonic acid, an isobutylene-maleic anhydridecopolymer, carboxymethyl cellulose, alginic acid, carrageenan,polyaspartic acid, polyglutamic acid, polyvinyl amine, polydiallyldimethyl ammonium hydroxide, polyacrylamidopropyl trimethyl ammoniumhydroxide, polyamino propanol vinyl ether, polyallylamine, chitosan,polylysine, polyglutamine and copolymers or mixtures thereof.

Exemplary superabsorbent materials can include a polymer selected fromthe group consisting of polycarbophil, polycarbophilic calcium,polymethacrylic acid, polyacrylic acid, and mixtures thereof.Polycarbophil is a superabsorbent polymer is capable of absorbing andretaining large quantities of water. Polycarbophil is a high molecularweight acrylic acid polymer cross-linked with divinyl glycol, and issold under the tradename, NOVEON® AA-1, by Lubrizol Corporation OH, USA.It is understood that 1 gram of polycarbophil can absorb about 62 gramsof water. Polycarbophil is stable and does not undergo hydrolysis oroxidation under normal conditions. Calcium salts of polycarbophil(polycarbophilic calcium) can be used and are available commerciallyunder the tradename NOVEON® CA-1 or CA-2 from Lubrizol Corporation OH,USA. Other exemplary superabsorbent materials include Carbopol®polymers, which are acrylic acid polymers cross-linked with, forexample, allyl ethers of pentaerythritol, for example, Carbopol® 71G (acarbomer homopolymer type A), Carbopol® 971P (a carbomer homopolymertype A), and Carbopol® 974 (a carbomer homopolymer type B), each ofwhich is available from Lubrizol Corporation, OH, USA.

The superabsorbent material provides two functions. First, when theformulation containing the superabsorbent material (for example,polycarbophil) is crushed and combined with solvent (for example, water)for parenteral injection, the superabsorbent material rapidly absorbsthe water, swells and forms a hard gel thus preventing injection. Inaddition, depending upon the amount of solvent added, all of the solventmay be absorbed leaving no residual solvent that can be administered.Second, if the formulation is crushed and snorted into a nostril thesuperabsorbent material absorbs the liquid in the nostril causing thesuperabsorbent material to swell. Not only does the swelling causediscomfort but also prevents the drug disposed within the formulationfrom being rapidly released (for example, within less than 30 minutes).

In general, the proportion of the superabsorbent material in the corevaries from about 10% (w/w) to about 70% (w/w) of the core, morepreferably from about 30% (w/w) to about 50% (w/w) of the core.Furthermore, the superabsorbent material in the core varies from about2% (w/w) to about 20% (w/w) of the final intact formulation, morepreferably from about 4% to about 14% of the final intact formulation,more preferably from about 6% to about 12% of the final intactformulation.

In addition, relative to the intact formulation, the volume of the coreconstitutes from about 5% to about 40% of the intact formulation, fromabout 10% to about 30% of the intact formulation, or from about 15% toabout 20% of the intact formulation. In certain embodiments, the volumeof the core constitutes at least 30%, at least 20%, or at least 15% ofthe final volume of the resulting intact formulation.

In addition to the superabsorbent material, the core can comprise otherexcipients and manufacturing aids including, for example, one or more ofgranulation aids (for example, xanthan gum, polyethylene oxide,polyvinylpyrollidone, cellulose and sucrose derivatives, and mixturesthereof), a lubricant (for example, magnesium stearyl fumarate,magnesium stearate, and stearic acid), a glidant (for example, colloidalsilicon dioxide and talc), a dye (for example, iron oxide), and a filler(for example, microcrystalline starch).

In addition, the core can comprise controlled release microparticlescontaining a pharmaceutically active agent of interest. Compositions ofexemplary controlled release microparticles and methods for theirmanufacture are described in Section C below.

In certain embodiments, the core is monolithic, and optionally comprisesmicroparticles disposed therein. It is understood, however, that undercertain circumstances the core can comprise a plurality of differentrelease matrices, which can be, for example, in the form of a bilayer ora multilayer that contains two, three or more layers. One of the layerscan act can as an immediate release layer and another layer can act as acontrolled release layer. Alternatively, at least two of the layers canhave controlled release properties. In one embodiment, one layer canrelease one pharmaceutically active agent and another layer can releasea different pharmaceutically active agent, which can be released at thesame or at different rates. In another embodiment, one layer can releaseone pharmaceutically active agent at one rate and another layer canrelease the same pharmaceutically active agent at a different rate(i.e., faster or slower than the first layer).

B. Considerations for the Coat

The coat, when present, performs an important function in the operationof the formulation of the invention. The coat provides a hard outershell that (i) resists damage by crushing or chewing, (ii) resists therelease of drug as the pH of the extraction media varies (for example,when the formulations are combined with conventional carbonatedbeverages), (iii) resists the release of drug in the presence of alcoholin the extraction media even at levels that exceed the alcohol contentof alcoholic beverages, and (iv) permits permeation by solvent to permitthe release of drug disposed within microparticles located in the coreand/or the coat. Under normal use, the coat still provides a rigidnet-like structure that encapsulates the core and prevents thesuperabsorbent material in the core from swelling.

In certain embodiments, the coat comprises a controlled release agent.Alternatively, or in addition, the coat is a controlled release coating.Exemplary controlled release agents and coatings can be selected fromthe group consisting of acetate succinate, a polyvinyl derivative (forexample, polyvinyl alcohol, polyvinyl acetate, polyvinyl acetatephthalate, a copolymer of vinyl acetate and vinyl pyrrolidone, acopolymer of vinyl acetate and crotonic acid, polyvinylpyrollidone),polyethylene oxide, polyacrylic acid, polysaccharides (for example,modified starch, cross-linked high amylose starch, hydroxypropyl starch,hydroxypropyl methylcellulose phthalate, cellulose and cellulosederivatives (for example, microcrystalline cellulose, carboxymethylethylcellulose, cellulose acetate, methylcellulose, ethylcellulose,hydroxypropyl cellulose, hydroxypropylmethyl cellulose, cellulosephthalate, cellulose acetate, cellulose acetate phthalate, celluloseacetate propionate, cellulose-acetate succinate, cellulose acetatebutyrate, cellulose-acetate trimellitate)), poloxamer, povidone, alginicacid, sodium alginate, polyethylene glycol, polyethylene glycolalginate, gums (for example, xanthan gum), polymethacrylates (including,for example, a copolymer of methacrylic acid and methyl-methacrylate,and a copolymer of methacrylic acid and ethyl acrylate), a copolymer ofmethacrylic acid and ethyl acrylate, a copolymer of polymethyl vinylether and malonic acid anhydride, a copolymer of polymethyl vinyl etherand malonic acid or the ethyl-, isopropyl-, n-butylesters thereof, zein,and mixtures of the foregoing.

Further examples of controlled release film-coating polymers include,but are not limited to, methylcellulose, ethylcellulose (for example,Aquacoat® type from FMC Corp.), methylhydroxyethylcellulose,methylhydroxypropylcellulose (for example, Pharmacoat® type from ShinEtsu Corp.), ethylhydroxyethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose, carboxymethylcellulose ormethylcarboxymethylcellulose, acrylic polymers, polyvinylacetates,polyvinyl chlorides, polymethylmetacrylates or a terpolymer ofvinylchloride, vinylalcohol and vinylacetate,hydroxypropylmethylcellulose phthalate (for example, HP type from ShinEtsu), hydroxypropylmethylcellulose acetate succinate (for example,Aqoat from Shin Etsu), cellulose acetate phthalate (for example,Aquacoat CPD from FMC Corp. or C-A-P NF from Eastman Chemical),polyvinyl acetate phthalate (for example, Sureteric from Colorcon),carboxymethylethylcellulose, and co-polymerized methacrylicacid/methacrylic acid methyl esters (for example, Eudragit fromDegussa/Evonik Industries or Kollicoat from BASF or Acryl-Eze fromColorcon or Eastacryl from Eastman Chemical).

In one embodiment, Kollidon® SR (a powder consisting of polyvinylacetate (8 parts, w/w) and polyvinyl pyrrolidone (2 parts, w/w)) is usedin combination with xanthan gum. Kollidon® SR is available from BASF,ON, Canada. In another embodiment, the coat can be, for example,Eudragit® L30D 55, available from Degussa/Evonik Industries, NJ, USA.Furthermore, it is understood that, depending upon the release kineticsdesired, the same controlled release agents and coatings can be disposedwithin or can coat the microparticles described below in Section C.

In addition, the coat can comprise one or more of a viscosity increasingagent (for example, xanthan gum, polyethylene oxide,polyvinylpyrollidone, cellulose and sucrose derivatives), a lubricant(for example, sodium stearyl fumarate, magnesium stearate and stearicacid), a glidant (for example, colloidal silicon dioxide and talc), anda dye (for example, iron oxide).

In some embodiments, the coat may comprise a plasticizer. Examples ofplasticizers include, but are not limited to, cetanol, triacetin, citricacid esters, phthalic acid esters, dibutyl succinate, acetylatedmonoglyceride, acetyltributyl, acetyltributyl citrate, acetyltriethylcitrate, benzyl benzoate, calcium stearate, castor oil, cetanol,chlorebutanol, colloidal silica dioxide, dibutyl phthalate, dibutylsebacate, diethyl oxalate, diethyl malate, diethyl maleate, diethylmalonate, diethyl fumarate, diethyl phthalate, diethyl sebacate, diethylsuccinate, dimethylphthalate, dioctyl phthalate, glycerin,glyceroltributyrate, glyceroltriacetate, glyceryl behanate, glycerylmonostearate, hydrogenated vegetable oil, lecithin, leucine, magnesiumsilicate, magnesium stearate, polyethylene glycol, propylene, glycol,polysorbate, silicone, stearic acid, talc, titanium dioxide, triacetin,tributyl citrate, triethyl citrate, zinc stearate, PEG (polyethyleneglycol), and the like.

In one embodiment, the coat contains Kollidon® SR and xanthan gum asrelease controlling agents, colloidal silicon dioxide as a glidant, andsodium stearyl fumarate as a lubricant. Incorporation of Kollidon® SRand xanthan gum into the coat helps provide a controlled-release of thepharmaceutically active agent (for example, tramadol HCl), andsignificantly increases the mechanical strength of the resultingformulations making them harder to crush.

In addition, the coat can comprise controlled release microparticlescontaining a pharmaceutically active agent of interest. Compositions ofexemplary controlled release microparticles and methods for theirmanufacture are described in the following section.

C. Considerations for the Controlled Release Microparticles

As shown in FIGS. 1A-F, the formulations of the invention comprisescontrolled release microparticles disposed within the coat (FIGS. 1A and1D), the core (FIGS. 1B and 1E), or within both the core and the coat(FIGS. 1C and 1F). The controlled release microparticles containpharmaceutically active agent and facilitate the controlled release ofthe pharmaceutically active agent disposed therein. Depending upon theconfiguration chosen, the formulations can release the pharmaceuticallyactive agent over a prolonged period of time, for example, at least 6hours, at least 8 hours, at least 12 hours, at least 18 hours, or atleast 24 hours.

Although the controlled release particles may take a variety of forms,they have a number of features in common, which include (i) they havecontrolled release properties and (ii) they are of a size that makesthem hard to crush even when the formulations are crushed with aconventional pill crusher. The microparticles may have a core and acoat, where either or both provide controlled release properties.

The core of the microparticles can comprise the pharmaceutically activeagent and a variety of excipients, which include, for example, one ormore of, a spheronizing agent, a plasticizer, and a controlled releaseagent. Exemplary spheronizing agents include, for example,microcrystalline cellulose, ethyl cellulose, low substitutedhydroxypropylcellulose and dicalcium phosphate dihydate.Microcrystalline cellulose is preferred and is available commerciallyunder the tradename Avicel® PH101 from FMC BioPolymer, DE, USA.Microcrystalline cellulose forms a plastic and cohesive mass uponwetting, which is desirable for the successful production of sphericalgranules. Microcrystalline cellulose is considered to aid thespheronization process by absorbing water like a molecular sponge andhelps in the binding and lubrication of the moistened powder mass duringextrusion. During the spheronization process, moisture trapped in themicrocrystalline cellulose microfibrils adds plasticity to the extrudateand helps convert short round extrudates obtained by extrusion intospherical pellets. Different grades of microcrystalline cellulose arecommercially available, and a preferred grade suitable forextrusion-spheronization is Avicel® PH 101, because of its smallparticle size, low packing density and high water retentive capacity.

In addition, the core of the microparticles can contain a plasticizer.Exemplary plasticizers include, for example, Plasacryl available fromIMTech, PA, USA, and triethyl citrate available from Morflex, NC, USA.

In addition, the core of the microparticles optionally can contain acontrolled release agent that controls the release of thepharmaceutically active agent. Exemplary controlled release agents canbe selected from the group consisting of starch, starch derivatives,cellulose derivatives, xanthan gum, polyethylene glycol, polyvinylacetate, polyvinyl alcohol, and mixtures thereof. In a preferredembodiment, the controlled release excipient includes a starchderivative that is a cross-linked high amylose starch, which providesthe controlled release of the pharmaceutically active agent for at least12 hours, for at least 18 hours, or for at least 24 hours. Thecross-linked high amylose starch can be cross-linked with phosphorusoxychloride and/or can contain hydroxypropyl side chains. In certainembodiments, a suitable controlled release agent is commerciallyavailable from Labopharm, Inc., Laval, Canada, under the trademarkCONTRAMID®. The synthesis of the CONTRAMID® excipient is described inU.S. Pat. No. 6,607,748.

The core of the microparticles containing a pharmaceutically activeagent can be prepared by a variety of methods, including, for example,wet granulation and extrusion-spheronization. During wet granulation,microparticles are prepared using, for example, a fluid bed rotorgranulator. The wet granulation process comprises, for example, (i)wetting the powder to form wet granules; (ii) exposing the wet granulesto tumbling or spheronization, and (iii) drying the product of step(ii). Alternatively, the pellets can be produced byextrusion-spheronization, which has the advantage of being highlyreproducible, easy to scale up, cost effective, and producessubstantially perfect spherical microparticles. Extrusion-spheronizationcomprises, for example, (i) wetting the powder blend with an aqueous ororganic solution generally containing a binder to form a wet homogeneousmass suitable for wet extrusion, (ii) extruding the wet mass to formcylindrical extrudates of uniform shape and size, and (iii) spheronizingthe wet extrudates using a spheronizer, where, for example, a fastspinning disc, breaks the extrudates into smaller microparticles androunds them to form spheres.

The cores of the microparticles can be coated with a controlled-releasecoating that is sufficiently flexible to be deformed under compressionduring tablet formation without undergoing fracture. Suitable controlledrelease agents are described in the previous section. In one embodiment,the controlled release coating comprises polymethacrylate (e.g.,Eudragit® RS, available from Degussa/Evonik Industries, NJ, USA).Eudragit® RS30D grade, which is particularly useful is an aqueousdispersion (30% w/w) of a polymeric mixture of ethyl acrylate, methylmethacrylate, and trimethylammonioethyl methacrylate at a ratio of1:2:0.1 (w/w). The Eudragit® RS grade is designed to formwater-insoluble film coats for sustained release formulations. TheEudragit® RS grade forms a highly flexible film coat with lowpermeability. Another useful coating material includes Eudagrit® L30D55, available from Degussa/Evonik Industries, NJ, USA. Anothercontrolled release coating comprises ethyl cellulose sold under thetradename Surelease®. Another controlled release coating includesKollicoat SR, available from BASF Fine Chemicals. In one approach, thecore of the microparticles is coated using a fluid bed coater equippedwith a bottom spray.

The resulting particles, depending upon their composition and method offabrication have an average diameter in the range of from about 1 μm toabout 1000 μm. In certain embodiments, the microparticles have anaverage diameter of from about of 200 μm to about 900 μm, or from about300 μm to about 800 μm. In certain embodiments, the resultingmicroparticles have an average diameter of about 700 μm. In certainother embodiments the microparticles have an average diameter of fromabout 1 μm to about 400 μm, from about of 5 μm to about 300 μm, or fromabout 10 μm to about 200 μm. In certain embodiments, the resultingmicroparticles have an average diameter of about 100 μm.

D. Pharmaceutically Active Agents

It is understood that the compositions described herein can be used forthe delivery of one or more pharmaceutically active agents. In certainembodiments, the controlled release microparticles can contain one ormore pharmaceutically active agents. In addition, it is understood thatthe formulations of the invention can contain a number of differentmicroparticles, with one population of microparticles containing onepharmaceutically active agent and another population of microparticlescontaining a second, different pharmaceutically active agent.

Many pharmaceutically active agents can benefit from being deliveredusing the formulations described herein. The Controlled Substances Act(CSA), Title II of the Comprehensive Drug Abuse Prevention and ControlAct of 1970, places all substances that are regulated under existingFederal Law into one of five schedules based upon the substance'smedicinal value, harmfulness, and potential for abuse or addiction. Theformulations of the invention are preferably used to deliver those drugsclassified as Schedule II, III, IV and V drugs. Similarly, although anydrug in which there is a benefit in having controlled release of thedrug can be incorporated into formulations of the invention, theformulations described herein are particularly useful in the deliveryof, for example, CNS and respiratory stimulant agents, analgesics (forexample, opioid analgesics), hypnotic agents, anxiolytic agents, andagents with a narrow therapeutic index. For purposes of this invention,pharmaceutically active agents are intended to encompass salts, esters,and the prodrugs of the pharmaceutically active agents.

Exemplary opioid analgesics include, for example, alfentanil,buprenorphine, butorphanol, carefentanil, codeine, dezocine,diacetylmorphine, dihydrocodeine, dihydromorphine, diprenorphine,etorphine, fentanyl, hydrocodone, hydromorphone,β-hydroxy-3-methylfentanyl, levo α-acetylmethadol, levorphanol,lofentanil, meperidine, methadone, morphine, nalbuphine, oxycodone,oxymorphone, pentazocine, pethidine, propoxyphene, remifentanil,sufentanil, tilidine, tramadol hydrochloride, or a mixture thereof.

Exemplary hypnotics include, for example, benzodiazepines andnon-benzodiazepines. Exemplary benzodiazepines include, but are notlimited to, alprazolam, diazepam, flurazepam, loprazolam mexazolam,nitrazepam, and the like. Exemplary non-benzodiazepines include, but arenot limited to, barbiturates (for example, butobarbitone,phenobarbitone, or amylobarbitone) chlormethiazole, eszopiclone,ramelteon, zaleplon, zopiclone, zolpidem, and the like.

Exemplary anxiolytic agents include, but are not limited to,amphetamine, buspirone, barbiturates, benzodiazepines (for example,alprazolan, bromazepam, brotizolam, camazepam, chlordiazepoxide,clobazam, clonazepam, desalkylflurazepam, diazepam, flunitrazepam,flurazepam, lorazepam, lometazepam, medazepam, metaclazepam, midazolam,nitrazepam, nordazepam, oxazepam, pentylenetetrazole, prazepam,temazepam, tetrazepam, and triazolam) and the like.

Exemplary CNS and respiratory stimulatory agents include, but are notlimited to xanthines (for example, caffeine and theophylline),amphetamines (for example, amphetamine, benzphetamine hydrochloride,dextroamphetamine, dextroamphetamine sulfate, levamphetamine,levamphetamine hydrochloride, methamphetamine, and methamphetaminehydrochloride), and miscellaneous stimulants such as methylphenidate,methylphenidate hydrochloride, modafinil, pemoline, sibutramine, andsibutramine hydrochloride.

Pharmaceutically active agents with a narrow therapeutic index include,for example, amiodarone, amphotericin, cabamazepine, clozapine, digoxin,disopyramide, lithium carbonate, minoxidil, phenytoin, primidone,procainamide, quinidine, theophylline, valproic acid, and warfarin.

It will be appreciated that the amount of the pharmaceutically activeagent present in the abuse-resistant formulation depends upon thetherapeutic dose required in conventional tablets. In generally, eachpharmaceutically active agent is present in an amount ranging from about0.5 mg to about 900 mg by weight, from about 1 mg to about 700 mg byweight, from about 1 mg to about 600 mg by weight, from about 1 mg toabout 500 mg, from about 1 mg to about 400 mg, from about 1 mg to about300 mg, from about 1 mg to about 200 mg, and from about 10 mg to about200 mg. It is understood, however, that the actual dosage will dependupon the particular pharmaceutically active ingredient and its proposeduse.

The invention also provides a solid dosage form for the controlledrelease of a pharmaceutically active agent disposed therein. The soliddosage form comprises an admixture of a superabsorbent material (forexample, polycarbophil) and a plurality of controlled releasemicroparticles having a pharmaceutically active agent disposed therein.When the solid dosage form is exposed intact to an aqueous environment,the pharmaceutically active agent is released from the solid dosage formover a prolonged period of time. However, when the solid dosage form iscrushed to expose the interior of the core and exposed to an aqueousenvironment, the superabsorbent material swells to create a hard gelthat traps the microparticles, and the microparticles provide controlledrelease of the pharmaceutically active agent. The solid dosage form canbe coated or uncoated. Accordingly, it is understood that the featuresand components of the coated formulations described hereinabove are alsoapplicable to the solid dosage form.

It is understood that the intact compositions described herein can beproduced using techniques known to those in a formulary arts. Anexemplary protocol for producing controlled release tablets is describedin Example 1. It is understood, however, that other approaches can beused to make formulations of the invention. The formulations of theinvention preferably have a hardness in the range of from about 100 N toabout 500 N, or from about 150 N to about 400N, or from about 200 N toabout 400N, or from about 300 N to about 400 N, with a target hardnessof at least 200 N. Furthermore, the formulations of the invention maytake the form of capsules, caplets, tablets, or pills.

The formulations of the invention can be used to administer apharmaceutically active agent to a mammal, for example, a human, in needof the pharmaceutically active agent (for example, an opioid analgesicfor pain management). It is understood that the exact dosage will varydepending on the symptoms, age, body weight, severity of the disease tobe treated and can be optimized through routine experimentation known tothose of skill in the art.

EXAMPLES

Practice of the invention will be more fully understood from theforegoing examples, which are presented herein for illustrative purposesonly, and should not be construed as limiting the invention in any way.

Example 1 Preparation of Exemplary Tramadol Containing ControlledRelease Formulation

This Example describes an exemplary misuse preventative tablet and howit can be made. The formulation contains tramadol, an opioid drug usedfor the treatment of moderate to moderately severe pain, which iscapable of being abused and for which over exposure via misuse can leadto harmful side effects. The misuse preventative tablet described inthis Example contains 100 mg of tramadol HCl which, as can be seen fromExample 2, is released from the intact tablets over 24 hours Theformulation of the complete tablet is set forth in Table 1, and themanufacture of each of the components for the formulation appear in thefollowing sections of this Example.

TABLE 1 Mg/Tablet Component Core blend Coat blend Tramadol HCl 25.0 75.0Avicel PH 101 30.6 30.0 Contramid 0.7 2.1 Polycarbophil (Noveon AA-1)62.9 — Xanthan gum 20.6 241.6 Kollidon SR — 120.5 Eudragit RS 30D 5.717.1 Triethyl citrate 0.6 1.7 Plasacryl 0.9 2.6 Colloidal silicondioxide 0.75 2.5 Sodium stearyl fumarate 1.5 5.0 FD&C Blue #1 Aluminiumlake 11-13 0.08 — Opadry white 0.67 21.3

The formulation of Table 1 was prepared by a multi-step process, whichis outlined below in subsections A-D.

A. Manufacture of Tramadol Containing Controlled Release Microparticles

The formulation of uncoated microparticles is set forth in Table 2, andthe uncoated microparticles were produced as follows. The variouscomponents were mixed in a mixer for 3 minutes under low shearconditions. The dry blend then was wetted under agitation in the samemixer by gradually adding water until a homogeneous wet mass suitablefor extrusion was produced. The wet mass then was extruded at a constantspeed (45 rpm) using a Laboratory Multigranulator extruder model MG-55from LCI, Inc., NC, USA equipped with a dome die having a 0.6 mmdiameter hole and a fixed extrusion gap. The extrudes then werespheronized at a constant speed (1800 rpm) using a Marumerzier ModelQJ-230T from LCI, Inc., NC, USA. The wet microparticles were dried at45° C. in a fluid bed until a moisture content of about 2% was achieved.

TABLE 2 % by Weight in Uncoated Weight (g) Components Microparticles inBatch Tramadol HCl 70.0 2,800.0 Avicel PH-101 28.0 1,120.0 Contramid 2.080.0 Water — 600.0 Total 100.0 4000.0

The resulting microparticles then were coated with a controlled releasecoating and an Opadry II White containing film as described in Table 3.The microparticles were coated in a fluid bed coater. The microparticleswere film coated to a weight gain of between 7% and 15% using an aqueoussolution of Eudragid RS30C containing Plasacryl and triethyl citrate(TEC). Afterwards, a curing solution containing Opadry II White wasadded to provide a film around the Eudragit containing coat to reducethe likelihood of the microparticles sticking together.

TABLE 3 Dry Quantity Components substance (g) weighed (g) CoatingSolution for Microparticles Uncoated pellets — 1000.0 Eudragit RS 30D160.0 533.3 TEC 24.0 24.0 Plasacryl 16.0 80.0 Curing Solution forMicroparticles Opadry II White 18.0 18.0

The resulting controlled released microparticles had a mean diameter ofabout 700 μm as measured by an optical microscope.

B. Manufacture of Core Composition

In addition to the controlled release microparticles, the core containedpolycarbophil as well as several other components. The remainingexcipients for the core are set forth in Table 4, and were mixed andsubjected dry granulation in a roller compactor (Vector Corp.) under aroll speed of 5 rpm, a screw speed of 19 rpm, and a pressure of 800 psi.

TABLE 4 % by Weight in Quantity Components Core Granulation Weighed (g)Polycarbophil 59.80 1794.0 Avicel PH-101 19.85 595.5 Xanthan Gum 19.85595.5 Colloidal silicon dioxide 0.25 7.5 Sodium stearyl fumarate 0.257.5 Total 100.0 3000.0

The tramadol containing microparticles then were mixed with theremaining granulated core excipients to produce the formulation of thecore, which is set forth in Table 5.

TABLE 5 Formulation Composition Mg/ Granu- % of Core Blend Tablet lation(mg) Core g/batch Tramadol Containing 43.5 29.00 464.0 MicroparticlesGranulated Polycarbophil 104.7 62.58 69.79 1116.6 Excipients Xanthan gum20.72 Avicel PH 101 20.82 Colloidal 0.26 silicon dioxide Sodium stearyl0.26 fumarate Colloidal silicon dioxide 0.5 0.33 5.3 Sodium stearylfumarate 1.2 0.83 13.3 FD&C Blue #1 Aluminium 0.1 0.05 0.8 Lake 11-13Total 150.0 100.00 1600

C. Manufacture of Coat Composition

In addition to the controlled release microparticles, the coat containedKollidon® SR and xanthan gum as well as several other components. Theremaining excipients for the coat are set forth in Table 6, and weremixed and subjected to dry granulation in a roller compactor (VectorCorp.) under a roll speed of 5 rpm, a screw speed of 19 rpm, and apressure of 800 psi.

TABLE 6 % by Weight in Quantity Components Coat Granulation Weighed (g)Crospovidone (Kollidon ® SR) 33.17 995.1 Xanthan gum 66.33 1989.9Colloidal silicon dioxide 0.25 7.5 Sodium stearyl fumarate 0.25 7.5Total 100.00 3000.0

The tramadol containing microparticles then were mixed with theremaining granulated coat excipients to produce the formulation of thecoat, which is set forth in Table 7.

TABLE 7 Formulation Composition Mg/ Granu- % of Coat blend tablet lation(Mg) Coat g/batch Tramadol Containing 130.5 26.10 1409.4 MicroparticlesGranulated Kollidon ® SR 363.8 120.46 72.75 3928.3 Excipients Xanthangum 240.88 Colloidal 0.91 silicon dioxide Sodium stearyl 0.91 fumarateColloidal silicon dioxide 1.6 0.32 17.3 Sodium stearyl fumarate 4.2 0.8344.9 Total 500.0 100.00 5400.0

D. Tablet Manufacture

Dry-coated tablets then were prepared using a Dry-Cota 16-Station tabletpress from Manesty, UK. The core formulation was added to a first hopperin the tablet press and compressed into a core tablet. The coatformulation then was added to a second hopper in the tablet press andthe core and the coat were compressed together to form the dry coatedtablet. The resulting dry coated tablets then were film coated with asolution of Opadry II using a fully perforated pan coating machine(O'Hara, Mississauga, ON, CA). The formulation of film coated tablets isset forth in Table 8.

TABLE 8 Quantity Components weighed (g) Dry Coated Tablets 2000.0 OpadryII White solution (20%) 60.0

The resulting tablets had a hardness in the range of from about 300 N toabout 400 N. with a target hardness of about 350 N.

Example 2 Release Properties of Intact Tablets

The release kinetics of the intact tablets produced in Example 1 werestudied in this Example. In addition, the release kinetics were studiedwhen alcohol was included in the extraction media and also when the pHof the extraction media was varied.

Initially, tramadol release was measured using the rotating basketmethod (U.S.P. Type I Apparatus) as described in U.S.P. 30 at 100 roundsper minute, at 37±0.5° C., in 900 mL of potassium phosphate monobasic pH6.8 solution (buffer stage) during 24 hours. The results from threeexperiments are summarized in FIG. 2. As can be seen from FIG. 2, thetablets produced in Example 1 release tramadol over a 24 hour periodwith kinetics summarized in Table 9.

TABLE 9 Time % Tramadol Standard (hours) Release Deviation 0.5 4 0.4 1.08 0.7 2.0 17 1.6 4.0 31 2.6 7.0 46 2.9 9.0 55 2.8 12.0 64 2.3 16.0 731.8 20.0 80 1.2 24.0 85 1.0

From the release kinetics presented in FIG. 2 and summarized in Table 9,the tablets produced in Example 1, under the conditions tested, releasedTramadol over 24 hours with quasi-zero order release kinetics.

In addition, the effect of alcohol on the release kinetics were studiedunder the same conditions as before except the extraction solvent wasvaried to include water, 20% ethanol in water, 40% ethanol in water, 60%ethanol in water, 80% ethanol in water and 100% ethanol. The results areset forth in FIG. 3, which shows that over 6 hours, less than about 30%of the tramadol was released when the extraction solvent contained up to60% ethanol. The tablets performed similarly when exposed to water, 20%ethanol, 40% ethanol and 60% ethanol. However, about 50% of the tramadolwas released over 6 hours when the tablets were exposed to extractionsolvents containing 80% and 100% ethanol.

The results set forth in FIG. 3 demonstrate that the controlled releaseproperties of the tablets produced in Example 1 was maintained inextraction solvents containing 100% water or 100% ethanol. In somecases, for example, in the presence of 20% ethanol, the release rate waseven slower than in water. Furthermore, under the conditions tested,less than 20% of the Tramadol was released from the intact tablets in 30minutes when placed in water, 20% ethanol, 40% ethanol, 60% ethanol, 80%ethanol, or 100% ethanol. Accordingly, it appears that the formulationsof the invention are compatible with conventional alcoholic beverages.

In addition, the effect of pH on the release kinetics were studied underthe same conditions as before except the extraction solvent was variedto include water, phosphate buffer at pH 6.8, phosphate buffer at pH5.0, phosphate buffer at pH 3.0, and acidified water at pH 1.2. Theresults are set forth in FIG. 4, which shows that the controlled releaseproperties of the tablets produced in Example 1 were maintained as pHwas reduced to 1.2. It appears, however, that the rate of releaseincreased as pH decreased from 6.8 to 1.2. Accordingly, it appears thatthe formulations of the invention are compatible with various commonbeverages (for example, carbonated drinks) that have a pH of about 3.5.

Example 3 Release Properties of Bisected Tablets

This Example demonstrates that, under the conditions tested, the tabletsproduced in Example 1 can be bisected without destroying the controlledrelease properties of the tablet. In other words, dose dumping did notoccur when the tablets were broken in half.

Briefly, tablets produced in Example 1 were bisected in half. Therelease kinetics of the intact tablets and the halves of the bisectedtablets were measured in a U.S.P. Type I Apparatus. The results werenormalized for the bisected tablets and are summarized in FIG. 5. Thekinetics of tramadol release from an intact tablet and a bisected tabletin a Type I Apparatus are summarized in Table 10 and Table 11,respectively.

TABLE 10 Time % Tramadol Standard (hours) Release Deviation 0.5 4 0.41.0 9 0.9 2.0 20 1.2 4.0 38 1.6 7.0 55 2.7 9.0 64 3.5 12.0 72 4.0 16.079 4.4 20.0 84 4.8 24.0 90 6.6

TABLE 11 Time % Tramadol Standard (hours) Release Deviation 0.5 9 1.51.0 16 2.4 2.0 29 3.7 4.0 48 5.6 7.0 68 7.4 9.0 76 9.5 12.0 88 7.4 16.094 7.8 20.0 98 8.2 24.0 100 8.5

FIG. 5 demonstrates that both the intact tablet and the bisected tabletmaintain their controlled release properties and release tramadol over20-24 hours. The release profile for the bisected tablets was similar tothat of the intact tablets, however, it appeared that the bisectedtablets released the tramadol slightly faster than the intact tablets.For example, at the 12 hour time point, the bisected tablet released80-90% of the starting amount of tramadol whereas the intact tabletsreleased 65-75% of the tramadol.

Example 4 Release Properties of Crushed Tablets

This Example describes the performance of the tablets made in Example 1after crushing with a conventional pill crusher. In particular, theperformance of the crushed tablets was measured after being exposed to anumber of extraction solvents under different conditions.

Initially, the tablets produced in Example 1 were crushed with a pillcrusher and combined in a glass vial with 2 mL of water (a volumetypical for intravenous drug abuse and greater than the volume typicallyavailable if the crushed tablet is mixed with food). The experiment wasperformed using 4 different lots of tablets. Once the crushed tablet wascombined with 2 mL of water, a hard gel was created within 20-30 secondsat the bottom of each leaving no available liquid that could be drawninto a syringe. As shown in FIG. 6, the vials could be inverted and thehard gels remained at the bottom of each vial. In FIG. 6, the first vialcontained 2 mL of water and vials 2-5 (inverted) contained crushedtablets from four separate lots (denoted Lots 1-4) each combined with 2mL of water. In each case, the gel produced was rigid enough to remainat the bottom of the vial even when inverted.

In addition, the ability to extract tramadol from the tablets producedin Example 1 was tested under different conditions after each tablet hadbeen crushed with a pill crusher. Briefly, the crushed tablet wascombined with 10 mL of extraction media (water, acid, base, or alcoholcontaining solvent) in a vial. The solution was heated to the specifiedtemperature (room temperature (RT), 50° C., 75° C., or 100° C.) andagitated mechanically for 15 minutes using a wrist action Burrellagitator. It was found, however, than no residual supernatant wasproduced. FIG. 7 shows seven inverted vials, each containing a hard gelproduced after a tablet prepared in Example 1 had been crushed in a pillcrusher and exposed to 10 mL of extraction media and incubated undervarious conditions, which included (1) water at room temperature for 15minutes (Vial 1, FIG. 7), (2) water at 50° C. for 15 minutes (Vial 2,FIG. 7), (3) water at 75° C. for 15 minutes (Vial 3, FIG. 7), (4) waterat 100° C. for 15 minutes (Vial 4, FIG. 7), (5) acidic media (acidifiedwater) at room temperature for 15 minutes (Vial 5, FIG. 7), (6) basicmedia (sodium hydroxide pH 10) at room temperature for 15 minutes (Vial6, FIG. 7), and (7) 40% ethanol at room temperature for 15 minutes (Vial7, FIG. 7). As can be seen in FIG. 7, all of the conditions testedresulted in formation of hard gels that remained at the bottom of eachvial upon inversion. There was no residual supernatant produced by thisprocess and so it was not possible to measure how much tramadol, if any,had been released from the formulation.

In another experiment, the release of tramadol was measured from tabletsproduced according to Example 1 after they had been crushed and exposedto solutions containing different concentrations of ethanol (20%, 40%and 60% ethanol). Briefly, the tablets were crushed and the amount ofdrug release into 900 mL of extraction media in a U.S.P. Type IApparatus with stirring at 100 rpm at 37° C. over 30 minutes. Theresults are summarized in the bar chart appearing in FIG. 8. Inaddition, the extraction of tramadol from commercially available UltramER was measured once the Ultram ER had been crushed and exposed to waterunder the same conditions as those used for the tablets produced inExample 1.

The results summarized in FIG. 8 show what there is no dose dumping oftramadol from the tablets of the invention when exposed to 900 mL ofwater, 20% ethanol, 40% ethanol or 60% ethanol. Under the conditionstested, less than 20% of the tramadol was released after 30 minutes. Incontrast, when commercially available Ultram ER was tested under thesame conditions using water as the extraction media, approximately 80%of the tramadol was released.

In another experiment, the release of tramadol was measured from tabletsproduced according to Example 1 after they had been crushed and exposedto extraction media having different pH values, which included water,phosphate buffer at pH 6.8, phosphate buffer at pH 5, phosphate bufferat pH 3, and acidified water at pH 1.2. The tablets were crushed and theamount of drug release into 900 mL of extraction media in a U.S.P. TypeI Apparatus with stirring at 100 rpm at 37° C. over 30 minutes. Theresults are summarized in the bar chart appearing in FIG. 9. Inaddition, the extraction of tramadol from commercially available UltramER was measured once the Ultram ER had been crushed and exposed to waterunder the same conditions as those used for the tablets produced inExample 1.

The results summarized in FIG. 9 show that, under the conditions tested,there was no dose dumping of tramadol when incubated in 900 mL ofextraction media (including water, phosphate buffer at pH 6.8, pH 5.0 orpH 3.0, and acidified water at pH 1.2). It is noted, however, that,under the conditions tested, as pH decreased the amount of releasedtramadol increased. For example, in water, less than 20% of the tramadolwas released. In contrast, when commercially available Ultram ER wastested under the same conditions using water as the extraction media,approximately 100% of the tramadol was released. In phosphate buffer atpH 6.8, 5, and 3, approximately 30-35% of the tramadol was released fromthe tablets of the invention, and in acidified water at pH 1.2approximately 65% of the tramadol was released.

Example 5 Pharmacokinetic Properties of Tramadol Tablets

The pharmacokinetic properties of the 100 mg tablets prepared in Example1 were assessed in a single dose, randomized, crossover study in 18healthy adults under both fasting conditions and fed conditions. Afteradministration, plasma samples were harvested periodically, and theconcentration of tramadol present in the plasma was measured via liquidchromatography-tandem mass spectrometry.

The results were plotted in FIGS. 10A and 10B, where the mean plasmaconcentrations of tramadol present in the plasma under fastingconditions is shown in FIG. 10A and the mean plasma concentrations oftramadol present in the plasma under fed conditions is shown in FIG.10B. The median T_(max) (hours) was 6.0 hours for both the fed andfasted conditions. The C_(max) (ng/mL) was 120±32 ng/mL and 154±41 ng/mLunder fasted and fed conditions, respectively. The T_(1/2) (hours) was8.4±2.9 hours and 6.8±2.1 hours following fasted and fed administration,respectively. The AUC_(0-t) (ng·h/mL) was 2556±1026 and 2746±1057 forthe fasted and fed states, respectively, and the AUC_(0-∞)(ng·h/mL) was2703±1109 and 2829±1119 for the fasted and fed states, respectively.

Example 6 Exemplary Oxycodone Tablet

This Example describes the manufacture and testing of 40 mg oxycodoneHCl tablet (BID) having a core and a controlled release coating. Thecoat comprises microparticles that provide controlled release propertiesand reduce misuse of the oxycodone disposed within the microparticles.

The microparticles were produced by extrusion spheronization, whichproduces the microparticles, and then were coated by fluidized bedcoating. The resulting coated microparticles were blended with the coatmatrix excipients and then compressed around a pre-formed polycarbophylcore.

The composition of the oxycodone containing microparticles are set forthin Table 12.

TABLE 12 Ingredients Mg/tablet Avicel PH 101 72.000 Contramid 2.297Eudragit RS 30D 9.136 Triethyl citrate 1.365 Plasacryl 0.906 OxycodoneHCl 40.000

The resulting microparticles then were coated in a fluid bed coaterequipped with a bottom spray. The microparticles were film coated to aweight gain of 7% to 15% using an aqueous solution of Eudragid RS30Ccontaining Plasacryl and triethyl citrate (TEC). Afterwards, a curingsolution containing Opadry II White was added to provide a film aroundthe Eudragit containing coat to reduce the likelihood of themicroparticles sticking together.

The composition of the core and the coat is set forth in Table 13.

TABLE 13 Mg/tablet Ingredients Core blend Coat blend Total Oxycodone HCl(provided — 125.704 125.704 as microparticles) Avicel PH 101 13.749 —13.749 Contramid — 2.297 2.297 Polycarbophil (Noveon AA-1) 41.420 —41.420 Xanthan gum 13.749 34.451 48.200 Kollidon ® SR — 68.908 68.908Colloidal silicon dioxide 0.349 1.440 1.789 Sodium stearyl fumarate0.698 2.610 3.308 FD&C Yellow #6 Aluminium lake 0.035 — 0.035 Total70.000 233.113 303.113

The dry-coated tablets were prepared using a Dry-Cota 16-Station tabletpress from Manesty, UK. The core formulation was added to a first hopperin the tablet press and compressed into a core tablet. The coatformulation then was added to a second hopper in the tablet press andthe core and the coat were compressed together to form the dry coatedtablet. The resulting dry coated tablets then were film coated with asolution of Opadry II using a fully perforated pan coating machine(O'Hara, Mississauga, ON, CA).

The in vitro release properties of the resulting tablets were measuredin a U.S.P. Type I Apparatus in phosphate buffer pH 6.8 or watercontaining 40% ethanol. The release kinetics were measured on intacttablets (see, FIG. 11A) or crushed tablets (see, FIG. 11B), which hadbeen crushed by using a conventional pill crusher. FIG. 11B also showsthe release of oxycodone over time from Oxycontin tablets availablecommercially from Purdue Pharma. In addition, the release kinetics weremeasured for intact tablets in the presence of phosphate buffer pH 6.8,and for bisected tablets (half tablets) in the presence of phosphatebuffer pH 6.8 (see, FIG. 12). As shown in FIG. 12, the release profileswere substantially the same for the intact tablets and the bisectedtablets.

The intact tablets provided controlled release over 12 hours and therelease was not materially affected by the presence of 40% ethanol. Incontrast to the crushed Oxycontin tablets, neither the crushed nor thebisected tablets (half tablets) produced in accordance with theinvention released oxycodone by dose dumping, and no dose dumping wasseen in the presence of 40% ethanol.

Example 7 Exemplary Oxycodone HCl/Acetaminophen Tablet

This Example describes the manufacture and testing of a twice a daytablet (BID) containing 20 mg oxycodone HCl and 650 mg of acetaminophen.The tablet comprises a core surrounded by an enteric, controlled releasecoating (namely, Eudragit L30D55), where the core is in the form of abilayer.

The composition of the microparticles is set forth in Table 14.

TABLE 14 Ingredients Mg/Tablet Pellet composition (%) Oxycodone HCl 20.011.51 Cellulose microcrystalline 37.3 21.49 (Avicel PH101) Contramid 2.71.53 Lactose monohydrate 73.4 42.22 Eudragit NE 30D 20.0 11.51 Talc 20.011.51 Colloidal silicon dioxide 0.4 0.23 Total 173.8 100.00

The microparticles were produced by mixing the components set forth inTable 14 (except for the Eudragit NE 30D and Talc). The resultingmixture was subjected to extrusion and spheronization, and the resultingmicroparticles were coated with the Eudragit NE 30D and talc in a fluidbed coater equipped with a bottom spray. The core of the tablet was abilayer. The oxycodone containing microparticles were incorporated inthe slow release layer of the bilayer whereas the acetaminophen, asCOMPAP® which was in free form and not incorporated into microparticles,was present in both the rapid release layer and the slow release layer.

The composition of the bilayer core is set forth in Table 15.

TABLE 15 Tablet composition Ingredients (Mg) (%) First layer (rapidrelease) COMPAP ® (which includes acetaminophen) 288.89 89.72Microcrystalline Cellulose PH102 19.77 6.14 Croscaramellose sodiumAcDiSol 6.70 2.08 Colloidal silicon dioxide (Cab O sil) 1.68 0.52 Sodiumstearyl fumarate (Pruv) 4.83 1.50 FD&C Yellow #6 0.13 0.04 Total 322.00100.00 Second layer (slow release) Oxycodone (provided as oxycodonemicroparticles) 173.79 24.72 COMPAP ® (which includes acetaminophen)433.33 61.64 Carbopol 71 G 42.02 5.98 Xanthan gum 80 mesh 42.02 5.98Colloidal silicon dioxide (Cab O sil) 2.95 0.42 Sodium stearyl fumarate(Pruv) 8.86 1.26 Total 703.00 100.00

The bilayer core was prepared by mixing the components of each layer andthen compressing the materials in a Piccola™ bilayer tablet press (SMIInc., NJ, USA). The bilayer tablets had a hardness in the range of 190to 230 Newtons. The resulting bilayer core was then coated with EudragitL30D 55 by using a fully perforated pan coating machine (O'Hara,Mississauga, ON, CA). The resulting coating contained 82 mg of EudragitL30D 55, which accounted for 8% of the weight of the tablet.

The in vitro release kinetics of the resulting tablet were measured in aU.S.P. Type III Apparatus at 20 dpm after incubation in 0.1Mhydrochloric acid at pH 1.2 for 1 hour followed by incubation inphosphate buffer pH 6.8 for 11 hours. The results shown in FIG. 13indicate that no oxycodone was released from the tablet for about onehour when the tablet was in 0.1 M HCl. Once the pH was raised after onehour, the oxycodone was released with controlled release kinetics.

Example 8 Exemplary Once-a-Day 150 mg Tramadol Tablet

This Example describes the manufacture and testing of an exemplaryonce-a-day 150 mg tramadol HCl tablet, where the tablets have amonolithic core and a controlled release coating. The core comprises asuper absorbent polycarbophil and the controlled release coat comprisesxanthan gum and Kollidon. Tramadol containing microparticles aredisposed within both the core and the coat.

The composition of the microparticles is set forth in Table 16.

TABLE 16 Ingredients % composition Tramadol HCl 57.38 MCC Avicel PH 10124.60 Eudragit RS30D ® + Plasacryl ® + Triethyl citrate 16.39 OpadryII ® white 1.63 Total 100.00

Uncoated microparticles were produced as follows. Tramadol and Avicel PH101 were mixed in a mixer for 3 minutes under low shear conditions. Thedry blend then was wetted under agitation in the same mixer by graduallyadding water until a homogeneous wet mass suitable for extrusion wasproduced. The wet mass then was extruded at a constant speed (45 rpm)using a Laboratory Multigranulator extruder model MG-55 from LCI, Inc.,NC, USA equipped with a dome die having a 0.6 mm diameter hole and afixed extrusion gap. The extrudates then were spheronized at a constantspeed (1,800 rpm) using a Marumerzier Model QJ-230T from LCI, Inc., NC,USA. The wet microparticles were dried at 45° C. in a fluid bed until amoisture content of about 2% was achieved.

A portion of the resulting microparticles were coated with an aqueoussolution containing Eudragit RS 30D using a fluid bed coater. Themicroparticles were film coated to a weight gain of between 7% and 15%.Afterwards, a curing solution containing Opadry II White was added toprovide a film around the Eudragit containing coat to reduce thelikelihood of the microparticles sticking together.

The composition of the core granules is set forth in Table 17.

TABLE 17 Ingredients % Composition Polycarbophilic acid (Noveon AA-1)80.00 MCC PH-101 19.50 Colloidal silicon dioxide 0.25 Sodium stearylfumarate 0.25 Total 100.00

In addition to the controlled release microparticles, the core containedpolycarbophil as well as several other components. The remainingexcipients for the core were mixed and subjected dry granulation in aroller compactor (Vector Corp.) under a roll speed of 5 rpm, a screwspeed of 19 rpm, and a pressure of 800 psi. Then, uncoatedmicroparticles were mixed with the granulated core excipients to producethe core formulation.

The composition of the coat granules is set forth in Table 18.

TABLE 18 Ingredients % Composition Kollidon SR 49.75 Xanthan gum 49.75Colloidal silicon dioxide 0.25 Sodium stearyl fumarate 0.25 Total 100.00

The remaining excipients for the coat were mixed and subjected to drygranulation in a roller compactor (Vector Corp.) under a roll speed of 5rpm, a screw speed of 19 rpm, and a pressure of 800 psi. Then, coatedmicroparticles were mixed with the granulated coat excipients to producethe coat formulation.

The composition of the tablet is set forth in Table 19.

TABLE 19 Composition Ingredients % Mg/tablet Core formulation TramadolHCl microparticles 36.31 65.36 Core granules 62.44 112.39 Colloidalsilicon dioxide 0.50 0.90 Sodium stearyl fumarate 0.75 1.35 Total 100180 Coat formulation Tramadol HCl microparticles (film coated) 35.98196.09 Coat granules 63.02 343.46 Colloidal silicon dioxide 0.25 1.36Sodium stearyl fumarate 0.75 4.09 Total 100 545

Dry-coated tablets then were prepared using a Dry-Cota 16-Station tabletpress from Manesty, UK. The core formulation was added to a first hopperin the tablet press and compressed into a core tablet. The coatformulation then was added to a second hopper in the tablet press andthe core and the coat were compressed together to form the dry coatedtablet. The resulting dry coated tablets then were film coated with asolution of Opadry II using a fully perforated pan coating machine(O'Hara, Mississauga, ON, CA).

The in vitro release properties of the resulting tablets (both intactand crushed) were measured in a U.S.P. Type I Apparatus in phosphatebuffer pH 6.8. Three separate batches were tested. The results of invitro release from the intact tablets is shown in FIG. 14A and fromcrushed tablets is shown in FIG. 14B. The tablets were crushed using apill crusher. The results show that the intact tablets of the inventiondemonstrated a controlled release of tramadol over 24 hours in phosphatebuffer pH 6.8. Moreover, there was no dose dumping of tramadol from thecrushed tablets when exposed to the same dissolution conditions. Underthe conditions tested, less than 50% of the tramadol was released within60 minutes.

In addition, the in vitro release properties of the resulting tablets(both intact and crushed) were measured in a U.S.P. Type I Apparatus inwater or water containing 20% ethanol, 40% ethanol and 60% ethanol. Thesame three batches were tested. The results of in vitro release from theintact tablets in water containing 60% ethanol is shown in FIG. 15A andfrom crushed tablets in water containing 60% ethanol is shown in FIG.15B. Similar results were obtained when the water contained either 20%or 40% ethanol. The results show that alcohol concentrations up to atleast 60% have little or no effect on the release profiles. With respectto the crushed tablets, and as shown in FIG. 15B, less than 25% of theTramadol was released at 60 minutes in water containing 60% ethanol.

Example 9 Exemplary Once-a-Day 200 mg Tramadol Tablet

This Example describes the manufacture and testing of an exemplaryonce-a-day 200 mg tramadol HCl tablet, where the tablets have amonolithic core and a controlled release coating. The core comprisessuper absorbent polycarbophil and the controlled release coat comprisesxanthan gum and Kollidon. Tramadol containing microparticles aredisposed within the core and the coat.

The composition of four different lots of microparticles are set forthin Table 20.

TABLE 20 % composition Ingredients LOT 1 LOT 2 LOT 3 LOT 4 Tramadol HCl58.3 57.4 69.6 69.6 MCC Avicel PH 101 25.0 24.6 17.4 17.4 EudragitRS30D ® + 16.7 16.4 13.0 13.0 Plasacryl ® + Triethyl citrate Opadry IIwhite — 1.6 — — Total 100.0 100.0 100.0 100.0

The formulations of uncoated microparticles were produced as follows.Tramadol and Avicel PH 101 were mixed in a mixer for 3 minutes under lowshear conditions. The dry blend then was wetted under agitation in thesame mixer by gradually adding water until a homogeneous wet masssuitable for extrusion was produced. The wet mass then was extruded at aconstant speed (45 rpm) using a Laboratory Multigranulator extrudermodel MG-55 from LCI, Inc., NC, USA equipped with a dome die having a0.6 mm diameter hole and a fixed extrusion gap. The extrudates then werespheronized at a constant speed (1,800 rpm) using a Marumerzier ModelQJ-230T from LCI, Inc., NC, USA. The wet microparticles were dried at45° C. in a fluid bed until a moisture content of about 2% was achieved.

The resulting microparticles then were coated with an aqueous solutioncontaining Eudragit RS 30D using a fluid bed coater. The microparticleswere film coated to a weight gain of between 7% and 15%. Afterwards, forLot 2 only, a curing solution containing Opadry II White was added toprovide a film around the Eudragit containing coat.

The composition of the core granules is set forth in Table 21.

TABLE 21 Ingredients % Composition Polycarbophil (Noveon AA-1) 80.00 MCCPH-101 19.50 Colloidal silicon dioxide 0.25 Sodium stearyl fumarate 0.25Total 100.00

In addition to the controlled release microparticles, the core containedpolycarbophilic acid as well as several other components. The remainingexcipients for the core were mixed and subjected dry granulation in aroller compactor (Vector Corp.) under a roll speed of 5 rpm, a screwspeed of 19 rpm, and a pressure of 800 psi. Then, the coatedmicroparticles were mixed with the granulated core excipients to producethe core formulation.

The composition of the coat granules is set forth in Table 22.

TABLE 22 Ingredients % Composition Kollidon SR 33.2 Xanthan gum 66.3Colloidal silicon dioxide 0.25 Sodium stearyl fumarate 0.25 Total 100.0

The remaining excipients for the coat were mixed and subjected to drygranulation in a roller compactor (Vector Corp.) under a roll speed of 5rpm, a screw speed of 19 rpm, and a pressure of 800 psi. Then, coatedmicroparticles were mixed with the granulated coat excipients to producethe coat formulation.

The composition of four different lots of tablets is set forth in Table23.

TABLE 23 LOT 1 LOT 2 LOT 3 LOT 4 Ingredients % Mg/tab % Mg/tab % Mg/tab% Mg/tab Core Compositions Coated Tramadol HCl 47.62 85.72 45.87 87.1537.84 71.90 47.92 71.88 microparticles (50 mg Tramadol) Core granules51.13 92.03 52.81 100.34 60.91 115.73 50.83 76.25 Colloidal silicon 0.500.90 0.50 0.95 0.50 0.95 0.50 0.75 dioxide Sodium stearyl 0.75 1.35 0.751.43 0.75 1.43 0.75 1.13 fumarate Total Core 100 180 100 190 100 190 100150 Coat Compositions Coated Tramadol HCl 47.18 257.13 46.68 261.4138.50 215.60 35.94 215.64 microparticles (150 mg Tramadol) Coat granules51.82 282.42 52.32 292.99 52.15 292.04 63.06 378.36 Xanthan gum — — — —8.35 46.76 — — Colloidal silicon 0.25 1.36 0.25 1.40 0.25 1.40 0.25 1.50dioxide Sodium stearyl 0.75 4.09 0.75 4.20 0.75 4.20 0.75 4.50 fumarateTotal Coat 100 545 100 560 100 560 100 600 Tablet Weight 725 750 750 750

Dry-coated tablets then were prepared using a Dry-Cota 16-Station tabletpress from Manesty, UK. The core formulation was added to a first hopperin the tablet press and compressed into a core tablet. The coatformulation then was added to a second hopper in the tablet press andthe core and the coat were compressed together to form the dry coatedtablet. The resulting dry coated tablets then were film coated with asolution of Opadry II using a fully perforated pan coating machine(O'Hara, Mississauga, ON, CA).

The in vitro release properties of the resulting tablets (both intactand crushed) were measured in a U.S.P. Type I Apparatus in phosphatebuffer pH 6.8 or water. The results of in vitro release from intacttablets are shown in FIG. 16A and from crushed tablets is shown in FIG.16B. The tablets were crushed using a pill crusher. The results showthat the intact tablets of the invention demonstrated a controlledrelease of tramadol over 24 hours in phosphate buffer pH 6.8. Moreover,there was no dose dumping of tramadol from the crushed tablets whenexposed to the same dissolution conditions. Under the conditions tested,less than 50% of the tramadol was released within 60 minutes.

In addition, the in vitro release properties of the resulting tabletsfrom Lot 4 (both intact and crushed) were measured in a U.S.P. Type IApparatus in phosphate buffer pH 6.8 or water containing 20% ethanol,40% ethanol and 60% ethanol. The results of in vitro release from theintact tablets in buffer are shown in FIG. 17A and from crushed tabletsare shown in FIG. 17B. The results show that alcohol concentrations upto at least 60% have little or no effect on the release profiles. Withrespect to the crushed tablets, less than 15% of the tramadol wasreleased at 60 minutes in water containing 60% ethanol.

Example 10 Exemplary Twelve Hour 30 mg Hydrocodone Bitartrate Tablet

This Example describes the manufacture and testing of an exemplarytwelve hour tablet containing 30 mg of Hydrocodone bitartrate. Thetablets have a monolithic core and a controlled release coating. Thecore comprises super absorbent polycarbophil and the controlled releasecoat comprises xanthan gum and Kollidon. Hydrocodone containingmicroparticles are disposed within the coat. No active ingredient wasdisposed within the core.

The composition of the hydrocodone containing microparticles is setforth in Table 24.

TABLE 24 Ingredients % Composition Hydrocodone bitartrate 31.82 MCCAvicel PH 101 59.09 Eudragit RS30D ® + Plasacryl ® + Triethyl citrate9.09 Total 100.00

The microparticles were produced as follows. Hydrocodone bitartrate andAvicel PH 101 were mixed in a mixer for 3 minutes under low shearconditions. The dry blend then was wetted under agitation in the samemixer by gradually adding water until a homogeneous wet mass suitablefor extrusion was produced. The wet mass then was extruded at a constantspeed (45 rpm) using a Laboratory Multigranulator extruder model MG-55from LCI, Inc., NC, USA equipped with a dome die having a 0.6 mmdiameter hole and a fixed extrusion gap. The extrudes then werespheronized at a constant speed (1,800 rpm) using a Marumerzier ModelQJ-230T from LCI, Inc., NC, USA. The wet microparticles were dried at45° C. in a fluid bed until a moisture content of about 2% was achieved.

The resulting microparticles were coated with an aqueous solutioncontaining Eudragit RS 30D using a fluid bed coater. The microparticleswere film coated to a weight gain of between 7% and 15%.

The composition of the core granules is set forth in Table 25.

TABLE 25 Ingredients % Composition Polycarbophil (Noveon AA-1) 80.00 MCCPH-101 19.50 Colloidal silicon dioxide 0.25 Sodium stearyl fumarate 0.25Total 100.00

The core contained polycarbophil as well as several other components.These excipients were mixed and subjected dry granulation in a rollercompactor (Vector Corp.) under a roll speed of 5 rpm, a screw speed of19 rpm, and a pressure of 800 psi.

The composition of the coat granules is set forth in Table 26.

TABLE 26 Ingredients % Composition Kollidon SR 33.17 Xanthan gum 66.33Colloidal silicon dioxide 0.25 Sodium stearyl fumarate 0.25 Total 100.00

The remaining excipients for the coat were mixed and subjected to drygranulation in a roller compactor (Vector Corp.) under a roll speed of 5rpm, a screw speed of 19 rpm, and a pressure of 800 psi. Then, themicroparticles were mixed with the granulated coat excipients to producethe coat formulation.

The composition of intact tablets is set forth in Table 27.

TABLE 27 Composition Ingredients % Mg/tab Core Formulation Hydrocodonebitartrate microparticles — — Core granules 45.80 77.86 Klucel HF 52.9590.02 Colloidal silicon dioxide 0.50 0.85 Sodium stearyl fumarate 0.751.28 Total 100.00 170.00 Coat Formulation Hydrocodone bitartratemicroparticles 21.93 94.30 Coat granules 53.81 231.38 Avicel PH 10223.26 100.02 Colloidal silicon dioxide 0.25 1.08 Sodium stearyl fumarate0.75 3.23 Total 100.00 430.00

Dry-coated tablets then were prepared using a Dry-Cota 16-Station tabletpress from Manesty, UK. The core formulation was added to a first hopperin the tablet press and compressed into a core tablet. The coatformulation then was added to a second hopper in the tablet press andthe core and the coat were compressed together to form the dry coatedtablet. The resulting dry coated tablets then were film coated with asolution of Opadry II using a fully perforated pan coating machine(O'Hara, Mississauga, ON, CA).

The in vitro release properties of the resulting tablets (both intactand crushed) were measured in a U.S.P. Type I Apparatus in phosphatebuffer pH 6.8 or 0.1M hydrochloric acid pH 1.2. The results of in vitrorelease from the intact tablets are shown in FIG. 18A and from crushedtablets are shown in FIG. 18B. The tablets were crushed by using a pillcrusher. The results show that the intact tablets demonstrated acontrolled release of Hydrocodone bitartrate over 12 hours in phosphatebuffer pH 6.8 and in acid pH 1.2. However, the drug release rate in theacid was slightly higher than the release in phosphate buffer pH 6.8.Furthermore, there was no dose dumping of hydrocodone bitartrate fromthe crushed tablets when exposed to the same dissolution conditions.Under the conditions tested, less than 30%, and 55% of hydrocodone wasreleased within 60 minutes in phosphate buffer pH 6.8 and in acid pH1.2, respectively.

INCORPORATION BY REFERENCE

The entire disclosure of each of the patent and scientific documentsreferred to herein is incorporated by reference for all purposes.

EQUIVALENTS

Although the present invention has been illustrated by means ofpreferred embodiments thereof, it is understood that the inventionintends to cover broad aspects thereof without departing from the spiritand scope of the invention as defined in the appended claims.

1. A solid, compressed controlled release formulation, comprising: (a) acore comprising a superabsorbent material comprising a cross-linkedacrylic acid polymer characterized in that the cross-linked acrylic acidpolymer absorbs at least 15 times its own weight of water, thesuperabsorbent material comprising from 30% to 70% (w/w) of the core;(b) a controlled release coat surrounding the core; and (c) a pluralityof controlled release microparticles having a pharmaceutically activeagent disposed therein, wherein the microparticles are disposed withinthe core, the coat, or both the core and the coat, the formulationhaving a hardness from about 200 N to about 400 N, and wherein theformulation (i) when intact and exposed to an aqueous medium, thepharmaceutically active agent is released from the formulation over aprolonged period of time, (ii) when crushed to break the controlledrelease coat and exposed to 2 mL of water, the superabsorbent materialabsorbs all of the water and creates a hard gel that traps themicroparticles, whereupon the hard gel and the microparticles providecontrolled release of the pharmaceutically active agent disposed withinthe microparticles, and (iii) when broken and exposed to 900 mL of waterin a U.S.P. Type I Apparatus with stirring at 100 rpm for 30 minutes at37° C., less than about 50% by weight of the pharmaceutically activeagent originally present in the formulation before it was broken isreleased into the water. 2-39. (canceled)